Novel copy number variants and major limb reduction malformation: Report of three cases

Abstract

Limb reduction malformations are highly heterogeneous in their clinical presentation and so, predicting the underlying mutation on a clinical basis can be challenging. Molecular karyotyping is a powerful genomic tool that has quickly become the mainstay for the study of children with malformation syndromes. We describe three patients with major limb reduction anomalies in whom pathogenic copy number variants were identified on molecular karyotyping. These include a patient with hypoplastic phalanges and absent hallux bilaterally with de novo deletion of 11.9Mb on 7p21.1-22.1 spanning 63 genes including RAC1, another patient with severe Holt-Oram syndrome and a large de novo deletion 2.2Mb on 12q24.13-24.21 spanning 20 genes including TBX3 and TBX5, and a third patient with acheiropodia who had a nullizygous deletion of 102kb on 7q36.3 spanning LMBR1. We discuss the potential of these novel genomic rearrangements to improve our understanding of limb development in humans.